Project Summary/Abstract The prevalence of diabetes in the United States and world-wide is increasing dramatically, and new drugs that can protect or restore the function of insulin-producing pancreatic beta cells are urgently needed. For decades, diabetes drug discovery efforts have been hampered by two things: 1) the lack of abundant human beta cells for drug screening, and 2) the difficultly and expense of antibody-based assays to measure insulin secretion, the key indicator of beta cell function. The advent of beta cells derived from induced pluripotent stem cells (iPSC), as pioneered by Regenerative Medical Solutions (RMS), has opened an era of readily available beta cells for high-throughput screening (HTS). In parallel, at the Broad Institute, a novel luciferase- insulin fusion protein has been developed which has the demonstrated ability to accurately report insulin secretion from both immortalized rodent beta cell lines and primary human islets. We propose to combine these two technologies and thereby generate a much-needed screening tool consisting of iPSC-derived human beta-like cells that express the luciferase-insulin secretion reporter. RMS will engineer iPSC lines in which the reporter fusion protein is expressed under control of the human insulin promoter, such that it is subsequently cleaved and secreted in response to glucose and other secretagogues. In the subsequent Phase II project, we will develop methods to utilize these cells for medium- and high-throughput analysis of insulin secretion. The ultimate product, consisting of plates of reporter cells arrayed for compound screening, will represent a breakthrough platform for diabetes drug discovery and will be in high demand among RMS?s current and future customers.